Despite high vaccination coverage, Bordetella pertussis infection remains endemic and reports of increasing incidence in Australia, Canada, and Europe have been accumulating for the past twenty years. 2012 was the year with the highest whooping cough incidence in US and comparable outbreaks occurred also in the UK and Netherlands, in proportion of inhabitant numbers. Adaptation of the circulating pertussis strains to the vaccines, as well as the waning and/or suboptimal efficacy of vaccine-mediated immunity during adolescence has been proposed to account for resurgence, with infected adolescent and adult populations being the major transmitters of disease in community representing a potential reservoir for disease transmission to young children who are yet to be fully vaccinated. Furthermore, with the changing epidemiology, pertussis is increasingly becoming a real burden also in adults that experience long-lasting and very heavy cough periods of duration in weeks to months. This underscores the need to pursue research efforts on this disease in order to provide suitable protection to the most vulnerable populations.
One approach to developing new vaccines to prevent B. pertussis infection is to use live but attenuated Bordetella bacteria as an antigenic agent. Creating such vaccines remains a challenging endeavor because, in order to be safe and effective, the attenuation must remove toxicity while still preserving sufficient antigenicity and viability. Deletion or mutation of various B. pertussis components can be lethal to the bacteria, can render the bacteria unable to colonize a subject, and/or unable to induce a sufficiently protective immune response.
Previously, after much work and numerous failures, a highly attenuated B. pertussis strain named BPZE1 [deposited with the Collection Nationale de Cultures de Microorganismes (CNCM, Institut Pasteur, 25 Rue du Docteur Roux, F-75724, Paris, Cedex 15, France) on Mar. 9, 2006 under the number CNCM 1-3585] was developed. This strain produces enzymatically inactive pertussis toxin (PTX), no dermonecrotic toxin (DNT), and only trace amounts of tracheal cytotoxin (TCT). It was also shown to be genetically stable and safe in preclinical models and a 12 subject clinical trial. Given that B. pertussis virulence factors have evolved to promote colonization and prevent infection clearance (e.g., PTX inhibits neutrophils/macrophage recruitment and TCT induces ciliostasis), BPZE1's ability to colonize the lung was impaired. Nonetheless, it was surprisingly found that intranasally (i.n.) administered BPZE1 was able to colonize the lungs of mice sufficiently to induce a strong protective humoral and cellular immunity.